It is now well established that mental states have a profound influence on the general health status. Recent evidence has indicated that the immune and the neuroendocrine systems are functionally connected, and that this interaction is one through which mental states exert their influence. Thus the ability of mammalian organisms to mount an appropriate response to immune stimuli, depends at least in part on the presence or absence of CNS-mediated disturbances which alter pathways in the central nervous system. Reciprocally, changes in the activity of neuroendocrine systems [particularly the hypothalamic-pituitary-adrenal (HPA) axis] have profound consequences for mental and CNS functions. The messenger signals which subserve this communication network include interleukins (ILs), proteins released by stimulated macrophages; and hormones from the HPA axis, such as corticotrophin-releasing factor (CRF), vasopressin (VP) and oxytocin (OT); POMC-related peptides (ACTH and beta-endorphin); and corticosteroids. Nitric oxide (NO) has recently emerged as an essential transmitter within the brain. We have observed that injection of arginine derivatives which interfere with the activity of the enzyme responsible for NO formation [such as Nw/nitro-L-arginine- methylester (NAME)], significantly augmented the stimulatory action of peripherally administered IL-1beta,VP and OT on the HPA axis. All the Specific Aims described in this proposal are therefore designed to (a) test the hypothesis that endogenous NO exerts a restraining influence on the response of the HPA axis to immune signals, thereby expanding our initial findings that removal of endogenous NO augments the response of he HPA axis to specific secretagogues; and (b) investigate the mechanisms mediating this effect. All experiments will be carried out in rats of both genders, studied at various stages of sexual maturation. Specific Aim 1 will determine the role of endogenous NO in modulating the activity of the HPA axis in response to the acute injection of various ILs or endotoxin (LPS). Under Specific Aim 2, we will investigate the role of endogenous NO during circumstances of prolonged exposure to cytokines; we will use either paradigms in which ILs, LPS or antigens are infused chronically; or experimental models of inflammatory processes. Specific Aim 3 will investigate the mechanisms mediating the ability of arginine derivatives to augment the acute response of the HPA axis to ILs. Specific Aim 4 will investigate these mechanisms under conditions of chronic exposure to immune signals. Specifically, we will investigate these mechanisms under conditions of chronic exposure to immune signals. Specifically, we will investigate the role of changes in the hypothalamic levels,and release into the median eminence, of neuropeptides (CRF, VP, OT) and secretagogues (catecholamines, prostaglandins) regulating ACTH secretion. Because of the known influence of hormones of the HPA axis on brain functions, and because of the involvement of ILs in many CNS and mental diseases, our results ill provide useful information regarding the role of endogenous NO during both normal and pathological conditions.